EP1296669A1 - COMBINATION PREPARATION CONSISTING OF $g(V)-3-FATTY ACIDS AND OF CONJUGATED LINOLEIC ACIDS FOR TREATING IMMUNOLOGICALLY ORIENTED CLINICAL SIGNS - Google Patents

COMBINATION PREPARATION CONSISTING OF $g(V)-3-FATTY ACIDS AND OF CONJUGATED LINOLEIC ACIDS FOR TREATING IMMUNOLOGICALLY ORIENTED CLINICAL SIGNS

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Publication number
EP1296669A1
EP1296669A1 EP01929617A EP01929617A EP1296669A1 EP 1296669 A1 EP1296669 A1 EP 1296669A1 EP 01929617 A EP01929617 A EP 01929617A EP 01929617 A EP01929617 A EP 01929617A EP 1296669 A1 EP1296669 A1 EP 1296669A1
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Prior art keywords
fatty acids
esters
acids
pharmaceutically acceptable
cla
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EP01929617A
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German (de)
French (fr)
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EP1296669B1 (en
Inventor
Klaus Sommermeyer
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Fresenius Kabi Deutschland GmbH
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Fresenius Kabi Deutschland GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/60—Fish, e.g. seahorses; Fish eggs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/12—Mucolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics

Definitions

  • the present invention relates to the combined use of ⁇ -3 fatty acids on the one hand and / or their pharmaceutically acceptable salts and / or esters and / or a fish oil enriched in ⁇ -3 fatty acids in the triglyceride dressing and on the other hand of conjugated linoleic acids (CLA) and / or their pharmaceutically acceptable salts and / or esters for the production of pharmaceutical preparations with which, after oral and / or parenteral administration, an enhancement of the immunomodulating and anti-inflammatory effects can be achieved, which can be achieved in clinical pictures with a pronounced immunological component if the co-3 -Fatty acids and / or their derivatives without CLA and / or their derivatives.
  • CLA conjugated linoleic acids
  • Polyunsaturated fatty acids have long been known as an additive to oral and / or parenteral clinical nutrition to influence the course of the disease in critically ill patients.
  • the supply of unsaturated fatty acids through food is of both structural and functional importance for the body. Their structural importance lies in influencing the fatty acid pattern of the cell membranes and their functional importance in the provision of certain mediators, ie of hormone-like agents that modulate physiological processes.
  • the effects on the immune system, such as inflammatory and allergic reactions, and on the vascular system make polyunsaturated fatty acids interesting for a diet with therapeutic goals.
  • the unsaturated fatty acids are, depending on the position of their first double bond after the 9th, 6th or 3rd carbon atom (counted from the methyl end) in ⁇ -9-, ⁇ -6- and o 3-
  • Differentiated fatty acids are derived from the corresponding C ⁇ 8 fatty acids, namely ⁇ 9 fatty acids from oleic acid (cz ' s-9-octadecenoic acid), ⁇ s> -6 fatty acids from linoleic acid
  • the ⁇ -6 fatty acids are mainly in the form of linoleic acid (cig acid) or arachidonic acid (all-cw-5,8,11,14-eicosatetraenoic acid) and the ⁇ -3 fatty acids are mainly in the form of ⁇ - Linolenic acid (from vegetable oils and animal fats) as well as eicosapentaenoic acid (5,8,11,14,17-eicosapentaenoic acid) and docosahexaenoic acid (from fish oils).
  • the C o-acids arachidonic acid (AA) and eicosapentaenoic acid (EPA) are of particular importance for the effect on the immune status, because they are the precursors for the formation of the immunomodulatory eicosanoids, including the leukotrienes and prostanoids (prostaglandins, prostacyclins , Thromboxanes) are to be subsumed.
  • Both AA and EPA are predominantly incorporated into phospholipids of the cell membrane, from which they can be released by phospholipase A as required. Depending on the specific enzyme pattern of each cell, they are then converted into different eicosanoids. Two different metabolic pathways can be labeled, either the cyclooxygenase pathway or the lipoxygenase pathway, where both fatty acids compete with each other for the enzyme cyclooxygenase or lipoxygenase and can displace each other.
  • the prostanoids are formed via the cyclooxygenase pathway and the leukotrienes are formed accordingly via the lipoxygenase pathway.
  • AA under the action of lipoxygenase 4 series leukotrienes (e.g.
  • Prostanoids of the 3 series eg TXA 3 , PGE 3 PGI 3 .
  • Kidneys different patterns of action of eicosanoids, which is important in the therapy of seriously ill patients, e.g. in inflammatory processes, can be exploited.
  • the eicosanoids which can be formed in all mammalian cells (except erythrocytes) as a physiological response to a stimulus, work in extremely low concentrations. Because of their extremely short lifespan, however, they can only develop their effect in the cell where they were produced (autocrine) or, if need be, in neighboring cells (paracrine), so that they represent "local mediators". Their effect at the scene (a tissue or organ) occurs via chemotactic processes, whereby migration of effector cells, eg macrophages or neutrophilic granulocytes, to the focus of inflammation is set in.
  • effector cells eg macrophages or neutrophilic granulocytes
  • the ratio of ⁇ -3 to 6> 6 fatty acids is shifted in favor of the former, so that more eicosanoids are formed from ⁇ -3 fatty acids.
  • the inflammatory reaction is intensified, it can be caused by an increased formation of thromboxane A 3 and leukotriene B 5 from ⁇ 2> 3-fatty acids or EPA (at the expense of thromboxane A and leukotriene B 4 ) slow down due to the lower inflammatory effect of the EPA derivatives.
  • eicosanoids have a suppressive effect on the cellular immune response.
  • prostaglandin E and leukotriene B 4 formed from AA slow down the cellular defense reaction because these eicosanoids inhibit the production of interleukin 2, which is essential for the proliferation of T and B cells .
  • the corresponding eicosnanoids formed from EPA have a lower inhibitory effect compared to the eicosanoids formed from AA, so that with a higher proportion of eicosanoids from ⁇ -3 fatty acids a positive immunomodulatory net reaction results again.
  • Linoleic acid is a diunsaturated Cig fatty acid (c .s, c / 5-9.12-octadecadienoic acid ) which, in the form of its glycerol esters, is a constituent of practically all fatty oils.Linoleic acid is contained in sunflower oil, for example, to 61% and soybean oil, to 53%.
  • the invention was therefore based on the object of making available such preparations based on unsaturated fatty acids which are comparable to the immunomodulatory and anti-inflammatory effects of established preparations and which still have the advantages based on the formation of local mediators with regard to possible Have side effects.
  • This object was achieved in that ⁇ -3 fatty acids and / or their pharmaceutically acceptable salts and / or esters and / or a fish oil enriched in ⁇ -3 fatty acids in the triglyceride dressing in combination with conjugated linoleic acids (CLA) and / or their pharmaceuticals compatible salts and / or esters for the production of a medicament with immunomodulatory and anti-inflammatory activity against diseases with an immunological expression.
  • CLA conjugated linoleic acids
  • a metabolic intermediate reaction in the above biosynthesis of arachidonic acid from linoleic acid in a desaturation reaction composed of the enzyme ⁇ ⁇ - which catalyzes the desaturation reaction analog in the biosynthesis of eicosatetraenoic acid from ⁇ -linolenic acid desaturase.
  • CLA conjugated linoleic acids
  • the conjugated linoleic acids can be produced by isomerization from linoleic acid according to processes known per se. During the isomerization, the double bonds are first shifted from position 9 to position 10 or from position 12 to position 11, reversing the eis, eis into the eis, trans or trans, cw formation. With this shift, 8 different geometric isomers are theoretically possible. The double bonds can shift to other positions during the isomerization processes. Ice, tra / w formation conversions can occur simultaneously, so that a larger number of positional isomers are formed. One of these isomers specifically inhibits the zl 6 desaturation of linoleic acid. According to the invention, the CLA are used in the form of their free acids, but preferably in the form of their pharmaceutically acceptable esters, in particular as triglycerides.
  • ⁇ -3 fatty acids are found in fish oils in a triglyceride association.
  • Fish oils are particularly rich in EPA and DHA, but they can also contain docosapentaenoic acid (DPA).
  • DPA docosapentaenoic acid
  • the ⁇ -3 fatty acids are used in the form of their free acid or their pharmaceutically acceptable esters, but preferably in a triglyceride dressing.
  • the ⁇ -3 fatty acids used according to the invention preferably contain 15-50% by weight EPA, 10-50% by weight DHA and 2-8% by weight DPA in the triglyceride dressing. If the combination preparation is to be administered parenterally, it is particularly advantageous to use the ⁇ -3 fatty acids as fish oils enriched in the triglyceride dressing. The production of such highly refined fish oils is described, for example, in DE 37 22 540.
  • a therapeutically effective combination preparation is produced in such a way that the two active components, namely on the one hand ⁇ -3 fatty acids or their pharmaceutically acceptable esters or a fish oil enriched in ⁇ -3 fatty acids in a triglyceride dressing and on the other hand the conjugated linoleic acids (CLA) or their pharmaceuticals compatible esters or triglycerides are processed in a predetermined quantitative ratio to form a fat emulsion which is then administered to the patient either orally or parenterally.
  • CLA conjugated linoleic acids
  • the weight ratio of ⁇ -3 fatty acids and / or their pharmaceutically acceptable salts and / or esters to the conjugated linoleic acids (CLA) and / or their pharmaceutically acceptable salts and / or esters should preferably be in the range from 1: 5 to 10 : 1, most preferably 1: 1. If the ⁇ -3 fatty acids are used in the form of fish oil enriched in the triglyceride dressing and the CLA in the form of pharmaceutically acceptable esters, such as triglycerides, the ratio by weight of enriched fish oil to CLA or their esters is preferably in the range from 1: 5 to 20: 1.
  • ⁇ -3 fatty acids in the form of their derivatives preferably in the form of the ft> -3 fatty acid triglycerides
  • 0.5-40% by weight of a 25-80% Fish oil containing ⁇ -3 fatty acids in the triglyceride dressing and 0.5-20% by weight of CLA and / or their derivatives, preferably in the form of their triglycerides, are used as components.
  • the components are preferably added simultaneously or successively to predetermined substrates and homogeneously distributed therein.
  • Solid (in the case of oral application) or liquid foods are preferably used as substrates.
  • those foods are preferably used which themselves have a certain fat content, which should preferably be 5-30%.
  • Other preferred substrates are W / O emulsions and O / W emulsions. especially those that are suitable for infusions, as well as oral ones Application also soft gelatin capsules, in which the two effective components of the
  • An O / W infusion emulsion for parenteral administration additionally contains distilled water suitable for injections, 1-2% by weight egg lecithin and 2-3% by weight glycerin, 1-30% by weight, preferably 1.5% 20 wt .-%, the emulsion consists of the combination of ⁇ -3 fatty acids and CLA triglycerides according to the invention. If a fish oil is used as neutral oil, only CLA triglycerides need be added in the amount necessary to achieve the desired weight ratio of ⁇ -3 fatty acids to CLA due to the content of the ⁇ -3 fatty acid triglycerides contained therein.

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Abstract

The invention relates to the combined use of omega -3-fatty acids and/or their derivatives and of conjugated linoleic acids (CLA) and/or derivatives thereof for producing a preparation for use against clinical signs with pronounced immunological components.

Description

Kombinationspräparat aus 6 3-Fettsäuren und konjugierten Linolsauren zur Behandlung immunologisch geprägter Krankheitsbilder Combination preparation of 6 3-fatty acids and conjugated linoleic acids for the treatment of immunologically characterized clinical pictures
Die vorliegende Erfindung betrifft die kombinierte Nerwendung von einerseits ω-3 -Fettsäuren und/oder deren pharmazeutisch verträglichen Salzen und/oder Estern und/oder einem an ω-3- Fettsäuren im Triglyceridverband angereicherten Fischöl und andereseits von konjugierten Linolsauren (CLA) und/oder deren pharmazeutisch verträglichen Salzen und/oder Estern zur Herstellung von pharmazeutischen Präparaten, mit welchen nach oraler und/oder parenteraler Verabreichung eine Verstärkung der immunmodulierenden und antiinflammatorischen Wirkungen erreicht werden kann, die man bei Krankheitsbildern mit ausgeprägter immunologischer Komponente erzielt, wenn man die co-3 -Fettsäuren und/oder deren Derivate ohne CLA und/oder deren Derivate einsetzt.The present invention relates to the combined use of ω-3 fatty acids on the one hand and / or their pharmaceutically acceptable salts and / or esters and / or a fish oil enriched in ω-3 fatty acids in the triglyceride dressing and on the other hand of conjugated linoleic acids (CLA) and / or their pharmaceutically acceptable salts and / or esters for the production of pharmaceutical preparations with which, after oral and / or parenteral administration, an enhancement of the immunomodulating and anti-inflammatory effects can be achieved, which can be achieved in clinical pictures with a pronounced immunological component if the co-3 -Fatty acids and / or their derivatives without CLA and / or their derivatives.
Mehrfach ungesättigte Fettsäuren sind seit langem als Zusatz zu oral und/oder parenteral verabreichter klinischer Ernährung zur Beeinflussung des Krankheitsverlaufs bei kritisch Kranken bekannt. Die Zufuhr ungesättigter Fettsäuren über die Nahrung ist für den Körper sowohl von struktureller als auch funktioneller Bedeutung. Ihre strukturelle Bedeutung liegt in der Beeinflussung des Fettsäuremusters der Zellmembranen und ihre funktionelle Bedeutung in der Bereitstellung bestimmter Mediatoren, d.h von hormonähnlichen Wirkstoffen, welche physiologische Prozesse modulieren. Insbesondere die Wirkungen auf das Immunsystem, wie z.B. bei entzündlichen und allergischen Reaktionen, und auf das vaskuläre System machen mehrfach ungesättigte Fettsäuren für eine Ernährung mit therapeutischen Zielen interessant. Die ungesättigten Fettsäuren werden je nach der Position ihrer ersten Doppelbindung nach dem 9., 6. oder 3. Kohlenstoffatom (vom Methylende her gezählt) in ω-9-, ω-6- und o 3-Polyunsaturated fatty acids have long been known as an additive to oral and / or parenteral clinical nutrition to influence the course of the disease in critically ill patients. The supply of unsaturated fatty acids through food is of both structural and functional importance for the body. Their structural importance lies in influencing the fatty acid pattern of the cell membranes and their functional importance in the provision of certain mediators, ie of hormone-like agents that modulate physiological processes. In particular, the effects on the immune system, such as inflammatory and allergic reactions, and on the vascular system make polyunsaturated fatty acids interesting for a diet with therapeutic goals. The unsaturated fatty acids are, depending on the position of their first double bond after the 9th, 6th or 3rd carbon atom (counted from the methyl end) in ω-9-, ω-6- and o 3-
Fettsäuren unterschieden. Sie leiten sich von den entsprechenden Cι8-Fettsäuren ab, und zwar ά 9-Fettsäuren von der Ölsäure (cz's-9-Octadecensäure), <s>-6-Fettsäuren von der LinolsäureDifferentiated fatty acids. They are derived from the corresponding Cι 8 fatty acids, namely ά 9 fatty acids from oleic acid (cz ' s-9-octadecenoic acid), <s> -6 fatty acids from linoleic acid
(cz'.y, cts-9-12-Octadecadiensäure) und ω-3 -Fettsäuren von der α-Linolensäure (cis,cis,cis-9-l2-(cz ' .y, cts-9-12-octadecadienoic acid) and ω-3 fatty acids from α-linolenic acid (cis, cis, cis-9-l2-
15-Octadecatriensäure). Während die &>-9-Fettsäuren vom Menschen selbst synthetisiert werden können, sind ω-6- und ω-3 -Fettsäuren essentiell und müssen mit der Nahrung zugeführt werden. Dies beruht darauf, daß Säugetiere prinzipiel nicht mehr in der Lage sind, jenseits der l9-Position (Zählung vom carboxylseitigen Ende her) weitere Doppelbindungen in Fettsäuren einzuführen.15-octadecatrienoic acid). While the &> - 9 fatty acids can be synthesized by humans themselves, ω-6 and ω-3 fatty acids are essential and must be supplied with food. This is due to the fact that mammals are prinzipiel no longer in a position to introduce additional double bonds in fatty acids beyond the l 9 position (counting from carboxylseitigen end).
In der Nahrung liegen die ω-6-Fettsäuren hauptsächlich als Linolsäure (Cig-Säure) oder als Arachidonsäure (all-cw-5,8,11,14-Eicosatetraensäure) vor und die ω-3 -Fettsäuren hauptsächlich in Form von α-Linolensäure (aus Pflanzenölen und tierischen Fetten) sowie von Eicosapentaensäure (5,8,11,14,17-Eicosapentaensäure) und Docosahexaensäure (aus Fischölen).In food, the ω-6 fatty acids are mainly in the form of linoleic acid (cig acid) or arachidonic acid (all-cw-5,8,11,14-eicosatetraenoic acid) and the ω-3 fatty acids are mainly in the form of α- Linolenic acid (from vegetable oils and animal fats) as well as eicosapentaenoic acid (5,8,11,14,17-eicosapentaenoic acid) and docosahexaenoic acid (from fish oils).
Von diesen polyungesättigten Fettsäuren haben die C o-Säuren Arachidonsäure (AA) und Eicosapentaensäure (EPA) eine besondere Bedeutung für die Wirkung auf den Immunstatus, weil sie die Vorstufen zur Bildung der immunmodulatorisch wirkenden Eicosanoide darstellen, worunter die Leukotriene und Prostanoide ( Prostaglandine, Prostacycline, Thromboxane) zu subsummieren sind.Of these polyunsaturated fatty acids, the C o-acids arachidonic acid (AA) and eicosapentaenoic acid (EPA) are of particular importance for the effect on the immune status, because they are the precursors for the formation of the immunomodulatory eicosanoids, including the leukotrienes and prostanoids (prostaglandins, prostacyclins , Thromboxanes) are to be subsumed.
Sowohl AA als auch EPA werden überwiegend in Phospholipide der Zellmembran eingebaut, aus denen sie je nach Bedarf durch Phospholipase A freigesetzt werden können. In Abhängigkeit vom spezifischen Enzymmuster einer jeweiligen Zelle werden sie dann in verschiedene Eicosanoide umgewandelt. Dabei können zwei verschiedene Stoffwechselwege beschriften werden, entweder der Cyclooxygenaseweg oder der Lipoxygenaseweg, wo beide Fettsäuren jeweils um das Enzym Cyclooxy genäse bzw Lipoxygenase miteinander konkurrieren und sich gegenseitig verdrängen können. Über den Cyclooxygenaseweg werden die Prostanoide und entsprechend über den Lipoxygenaseweg die Leukotriene gebildet. Dabei werden aus AA unter der Einwirkung von Lipoxygenase Leukotriene der 4er Serie (z.B.Both AA and EPA are predominantly incorporated into phospholipids of the cell membrane, from which they can be released by phospholipase A as required. Depending on the specific enzyme pattern of each cell, they are then converted into different eicosanoids. Two different metabolic pathways can be labeled, either the cyclooxygenase pathway or the lipoxygenase pathway, where both fatty acids compete with each other for the enzyme cyclooxygenase or lipoxygenase and can displace each other. The prostanoids are formed via the cyclooxygenase pathway and the leukotrienes are formed accordingly via the lipoxygenase pathway. AA under the action of lipoxygenase 4 series leukotrienes (e.g.
LTB4, LTC4. LTD4) und aus EPA Leukotriene der 5er Serie (z.B. LTB5, LTC5, LTD5) gebildet, die sich in ihren Wirkungen unterscheiden. Entsprechend werden unter Einwirkung der Cyclooxygenase aus AA Prostanoide der 2er Serie (z.B. TXA2, PGE PGI2) und aus EPALTB 4 , LTC 4 . LTD 4 ) and EPA leukotrienes of the 5 series (eg LTB 5 , LTC 5 , LTD 5 ), which differ in their effects. Correspondingly, under the action of cyclooxygenase from AA series 2 prostanoids (eg TXA 2 , PGE PGI 2 ) and from EPA
Prostanoide der 3er Serie (z.B. TXA3, PGE3 PGI3) gebildet, die sich ebenfalls in ihrerProstanoids of the 3 series (eg TXA 3 , PGE 3 PGI 3 ) are formed, which are also in their
Wirkung unterscheiden. In Abhängigkeit vom Verhältnis von ω-3- zu #>-6-Fettsäuren und vom Stoffwechselweg ergeben sich dann in den Geweben bzw. Zellen (z.B. in Lungen, Leber,Differentiate effect. Depending on the ratio of ω-3 to #> - 6 fatty acids and the metabolic pathway, this results in the tissues or cells (e.g. in the lungs, liver,
Nieren) unterschiedliche Wirkungsmuster von Eicosanoiden, was bei der Therapie schwer kranker Patienten, z.B. bei entzündlichen Prozessen, ausgenutzt werden kann.Kidneys) different patterns of action of eicosanoids, which is important in the therapy of seriously ill patients, e.g. in inflammatory processes, can be exploited.
Die Eicosanoide, die in allen Zellen von Säugern (außer in Erythrozyten) als physiologische Reaktion auf einen Stimulus gebildet werden können, wirken schon in äußerst geringen Konzentrationen. Wegen ihrer äußerst kurzen Lebensdauer können sie ihre Wirkung jedoch nur in der Zelle entfalten, wo sie erzeugt wurden (autokrin) oder allenfalls noch in Nachbarzellen (parakrin), so daß sie „lokale Mediatoren" darstellen. Ihre Wirkung am Ort des Geschehens (einem Gewebe oder Organ) erfolgt über chemotaktische Vorgänge, wodurch eine Migration von Effektorzellen, z.B. Makrophagen oder neutrophilen Granulozyten, zum Entzündungsherd in Gang gesetzt wird. Bei schweren Krankheitsbildern, wie z.B. bei einer Sepsis, einer Psoriasis oder einer zystischen Fibröse kann es zu lokaler oder systemischer inflammatorischer Aktivierung des Stoffwechsels bis hin zu einer Hyperinflammation kommen. Als Folge davon können schwere Gewebsschäden bis hin zu einem Multiorganversagen auftreten.The eicosanoids, which can be formed in all mammalian cells (except erythrocytes) as a physiological response to a stimulus, work in extremely low concentrations. Because of their extremely short lifespan, however, they can only develop their effect in the cell where they were produced (autocrine) or, if need be, in neighboring cells (paracrine), so that they represent "local mediators". Their effect at the scene (a tissue or organ) occurs via chemotactic processes, whereby migration of effector cells, eg macrophages or neutrophilic granulocytes, to the focus of inflammation is set in. In severe clinical pictures, such as, for example, with sepsis, psoriasis or cystic fibrosis, it can become local or systemic inflammatory Activation of the metabolism can lead to hyperinflammation, which can result in severe tissue damage and even multi-organ failure.
Es konnte nun gezeigt werden, daß solche hyperinflammatorischen Prozesse, insbesondere bei Psoriasis und zystischer Fibröse, durch erhöhte Verabreichung von ω-3 -Fettsäuren gegenüber <2>-6-Fettsäuren abgeschwächt werden konnten. Der Grund ist darin zu sehen, daß die aus ω-3- Fettsäuren bzw. EPA gebildeten Eicosanoide eine geringere proinflammatorische Wirkung ausüben als solche aus &>-6-Fettsäuren bzw. AA gebildete Eicosanoide. Aus der vermehrten Nutzung von EPA zur Bildung der entsprechenden Eicosanoide auf Kosten einer entsprechenden Nutzung der AA zur Eicosanoidbildung resultiert dann ein antiinflammatorischer Nettoeffekt. Durch die Bereitstellung zusätzlicher ω-3 -Fettsäuren wird das Verhältnis von ω-3- zu 6>6-Fettsäuren zugunsten der ersteren verschoben, so daß mehr Eicosanoide aus ω-3 -Fettsäuren gebildet werden. Während also z.B. durch die Bildung von Thromboxan A2 und Leukotrien B4 aus 6 6-Fettsäuren bzw. AA die Entzündungsreaktion verstärkt wird, läßt sie sich durch eine vermehrte Bildung von Thromboxan A3 und Leukotrien B5 aus <2>3-Fettsäuren bzw. EPA (auf Kosten von Thromboxan A und Leukotrien B4) wegen der geringeren inflammatorischen Wirkung der EPA-Derivate bremsen.It has now been shown that such hyperinflammatory processes, especially in psoriasis and cystic fibrosis, could be weakened by increased administration of ω-3 fatty acids compared to < 2> -6 fatty acids. The reason for this can be seen in the fact that the eicosanoids formed from ω-3 fatty acids or EPA have a lower proinflammatory effect than those eicosanoids formed from>-6 fatty acids or AA. The increased use of EPA for the formation of the corresponding eicosanoids at the expense of a corresponding use of the AA for eicosanoid formation then results in a net anti-inflammatory effect. By providing additional ω-3 fatty acids, the ratio of ω-3 to 6> 6 fatty acids is shifted in favor of the former, so that more eicosanoids are formed from ω-3 fatty acids. So while, for example, through the formation of Thromboxane A 2 and leukotriene B 4 from 6 6-fatty acids or AA, the inflammatory reaction is intensified, it can be caused by an increased formation of thromboxane A 3 and leukotriene B 5 from <2> 3-fatty acids or EPA (at the expense of thromboxane A and leukotriene B 4 ) slow down due to the lower inflammatory effect of the EPA derivatives.
In größeren Mengen üben Eicosanoide eine supprimierende Wirkung auf die zelluläre Immunantwort aus. So bremsen aus AA (bzw. <w-6-Fettsäuren) gebildetes Prostaglandin E und Leukotrien B4 in hoher Konzentration die zelluläre Abwehrreaktion, weil von diesen Eicosanoiden die Produktion von für die Proliferation der T- und B-Zellen essentiellem Interleukin 2 gehemmt wird. Auch hier weisen die entsprechenden aus EPA gebildeten Eicosnanoide eine im Vergleich mit den aus AA gebildeten Eicosanoiden geringere Hemm Wirkung auf, so daß bei einem höheren Anteil von Eicosanoiden aus ω-3 -Fettsäuren wieder eine positive immunmodulatorische Nettoreaktion resultiert.In larger amounts, eicosanoids have a suppressive effect on the cellular immune response. For example, prostaglandin E and leukotriene B 4 formed from AA (or <w-6 fatty acids) slow down the cellular defense reaction because these eicosanoids inhibit the production of interleukin 2, which is essential for the proliferation of T and B cells , Here too, the corresponding eicosnanoids formed from EPA have a lower inhibitory effect compared to the eicosanoids formed from AA, so that with a higher proportion of eicosanoids from ω-3 fatty acids a positive immunomodulatory net reaction results again.
Insgesamt wären also bei oraler oder parenteraler Verabreichung von mehrfach ungesättigten Fettsäuren umso bessere immunmodulierende und antiinflammatorische Effekte bei kritischen Krankheitsbildern zu erwarten, je mehr aus ω-3 -Fettsäuren bzw. EPA stammende Eicosanoide im Verhältnis zu solchen aus &>-6-Fettsäuren bzw. AA stammenden Eicosanoiden gebildet werden. Es zeigte sich jedoch, daß sich über eine Einstellung des ω-3/ω-6- Verhältnisses mit der zugeführten Nahrung nur ein maximal erreichbares LTC /LTC4-Verhältnis - und damit der vorteilhafteste immunmodulierende Effekt - erreichen ließ, wenn eine Fettemulsion mit einem ω-3/ω-6-Verhältnis von 1 :2 eingesetzt wurde. Eine weitere Erhöhung des ω-3 -Fettsäureanteils in der verabreichten Fettemulsion erbrachte keine Verbesserung im LTC5/LTC4- Verhältnis. Der Grund ist darin zu suchen, daß die in stimulierten Zellen für die Bereitstellung der Eicosanoide „verbrauchte" Arachidonsäure ständig aus Linolsäure nachsynthetisiert wird. Linolsäure ist eine zweifach ungesättigte Cig-Fettsäure (c .s,,c/5-9,12-Octadecadiensäure) welche in Form ihrer Glycerinester Bestandteil praktisch aller fetten Öle ist. Linolsäure ist z.B. in Sonnenblumenöl zu 61% und in Sojaöl zu 53% enthalten. Linolsäure ist ferner für den Aufbau der Zellmembran unerläßlich und stellt für den Menschen eine essentielle Fettsäure dar.Overall, the more immunomodulatory and anti-inflammatory effects in critical clinical pictures would be expected with oral or parenteral administration of polyunsaturated fatty acids, the more eicosanoids derived from ω-3 fatty acids or EPA in relation to those from &> - 6 fatty acids or AA-derived eicosanoids are formed. However, it was found that by adjusting the ω-3 / ω-6 ratio with the food supplied, only a maximum achievable LTC / LTC 4 ratio - and thus the most advantageous immunomodulating effect - could be achieved if a fat emulsion with a ω-3 / ω-6 ratio of 1: 2 was used. A further increase in the ω-3 fatty acid content in the administered fat emulsion did not result in an improvement in the LTC 5 / LTC 4 ratio. The reason lies in the fact that the "spent" in stimulated cells for providing the eicosanoids, arachidonic acid is constantly resynthesized from linoleic acid. Linoleic acid is a diunsaturated Cig fatty acid (c .s, c / 5-9.12-octadecadienoic acid ) which, in the form of its glycerol esters, is a constituent of practically all fatty oils.Linoleic acid is contained in sunflower oil, for example, to 61% and soybean oil, to 53%.
Die derzeit in der Therapie eingesetzten Präparate mit entsprechenden immunmodulatorischen und antiinflammatorischen Wirkungen weisen, da sie nicht als lokale Mediatoren anzusehen sind, mehr oder weniger große Nebenwirkungen auf. Da aber die mit der Verabreichung von reinen ω-3 -Fettsäuren (ohne 6 6-Fettsäuren) zu erzielenden immunmodulatorischen und antiinflammatorischen Wirkungen nicht an die mit den etablierten Arzeimitteln derzeit erzielbaren Wirkungen heranreichen, konnten entsprechende Präparate auf co-3 -Fettsäurebasis nur unterstützend zu den etablierten Präparaten eingesetzt werden.The preparations currently used in therapy with corresponding immunomodulatory and anti-inflammatory effects have no effect because they cannot be regarded as local mediators are, more or less major side effects. However, since the immunomodulatory and anti-inflammatory effects that can be achieved with the administration of pure ω-3 fatty acids (without 6 6 fatty acids) do not come close to the effects that can currently be achieved with the established drugs, corresponding preparations based on co-3 fatty acids could only be supportive the established preparations.
Andererseits wären aber die wegen der lokal gebildeten und daher auch nur lokal wirkenden Mediatoren zu erwartenden äußerst geringen Nebenwirkungen dann ein entscheidender Fortschritt, wenn man Präparate zur Verfügung hätte, die auf der Grundlage von mehrfach ungesättigten Fettsäuren auch als Zusatz zu einem oral oder parenteral verabreichbaren Nahrungsmittel eine den etablierten Präparaten vergleichbare pharmazeutische Wirkung zeigen würden.On the other hand, the extremely low side effects to be expected due to the locally formed and therefore only locally acting mediators would be a decisive advance if preparations were available that were based on polyunsaturated fatty acids as an addition to an orally or parenterally administrable food would show a pharmaceutical effect comparable to the established preparations.
Der Erfindung lag daher die Aufgabe zugrunde, solche den immunmodulatorischen und antiinflammatorischen Wirkungen von etablierten Präparaten in ihrer Wirkung vergleichbare Präparate auf Basis von ungesättigten Fettsäuren zur Verfügung zu stellen, welche nach wie vor die auf der Bildung von lokalen Mediatoren beruhenden Vorteile im Hinblick auf evtl. Nebenwirkungen aufweisen.The invention was therefore based on the object of making available such preparations based on unsaturated fatty acids which are comparable to the immunomodulatory and anti-inflammatory effects of established preparations and which still have the advantages based on the formation of local mediators with regard to possible Have side effects.
Diese Aufgabe wurde dadurch gelöst, indem ω-3 -Fettsäuren und/oder deren pharmazeutisch verträgliche Salze und/oder Ester und/oder ein an ω-3 -Fettsäuren im Triglyceridverband angereichertes Fischöl in Kombination mit konjugierten Linolsauren (CLA) und/oder deren pharmazeutisch verträglichen Salzen und/oder Estern zur Herstellung eines Arzneimittels mit immunmodulatorischer und antiinflammatorischer Wirkung gegen Krankheiten mit immunologischer Ausprägung verwendet wurden.This object was achieved in that ω-3 fatty acids and / or their pharmaceutically acceptable salts and / or esters and / or a fish oil enriched in ω-3 fatty acids in the triglyceride dressing in combination with conjugated linoleic acids (CLA) and / or their pharmaceuticals compatible salts and / or esters for the production of a medicament with immunomodulatory and anti-inflammatory activity against diseases with an immunological expression.
Eine Stoffwechselzwischenreaktion bei der obigen Biosynthese von Arachidonsäure aus Linolsäure besteht in einer Desaturierungsreaktion unter Mitwirkung des Enzyms Δβ- Desaturase, welches auch die analoge Desaturierungsreaktion bei der Biosynthese von Eicosatetraensäure aus α-Linolensäure katalysiert. Es wurde nun überraschend gefunden, daß eine Kombination von ω-3 -Fettsäuren und konjugierten Linolsauren (CLA) die im Hinblick auf die erwünschten immunmodulatorischen und antiinflammatorischen Wirkungen „ungünstigen", von der <j 6-Fettsäure Arachidonsäure herstammenden Eicosanoide (Prostanoide der 2er Serie und Leukotriene der 4er Serie) in ihrer Bildung zu Gunsten der antiinflammatorisch wirkenden, aus ω-3 -Fettsäuren stammenden Mediatoren (Prostanoide derA metabolic intermediate reaction in the above biosynthesis of arachidonic acid from linoleic acid in a desaturation reaction, composed of the enzyme Δ β - which catalyzes the desaturation reaction analog in the biosynthesis of eicosatetraenoic acid from α-linolenic acid desaturase. It has now surprisingly been found that a combination of ω-3 fatty acids and conjugated linoleic acids (CLA) are the "unfavorable" eicosanoids derived from the <j 6-fatty acid arachidonic acid with regard to the desired immunomodulatory and anti-inflammatory effects (Prostanoids of the 2 series and leukotrienes of the 4 series) in their formation in favor of the anti-inflammatory mediators derived from ω-3 fatty acids (prostanoids of the
3er Serie und Leukotriene der 5er Serie) zurückdrängen konnte.3 series and leukotrienes of the 5 series).
Dadurch wird eine Wirkungsverstärkung der ω-3 -Fettsäuren erreicht, was dem Kombinationspräparat eine ausreichende Verstärkung der immunmodulatorischen und antiinflammatorischen Wirkungen verleiht, die denen der etablierten Pharmaka nahekommen, jedoch ohne deren Nachteile hinsichtlich der Nebenwirkungen.This results in an increase in the activity of the ω-3 fatty acids, which gives the combination preparation a sufficient increase in the immunomodulatory and anti-inflammatory effects which come close to those of the established pharmaceuticals, but without their disadvantages in terms of side effects.
Die konjugierten Linolsauren (CLA) lassen sich durch Isomerisierung aus Linolsäure nach an sich bekannten Verfahren herstellen. Bei der Isomerisierung werden zunächst die Doppelbindungen von Position 9 in die Position 10 oder von der Position 12 in die Position 11 unter Umkehrung der eis, eis- in die eis, trans- bzw. trans, cw-Formation verschoben. Bei dieser Verschiebung sind theoretisch 8 verschiedene geometrische Isomere möglich. Die Doppelbindungen können sich bei den Isomerisierungsvorgängen in weitere Positionen verschieben. Dabei können gleichzeitig eis, tra/w-Formationsumwandlungen auftreten, so daß eine größere Anzahl von Positionsisomeren entstehen. Eines dieser Isomere bewirkt die spezifische Hemmung der zl6-Desaturierung von Linolsäure. Die CLA werden erfindungsgemäß in Form ihrer freien Säuren, vorzugsweise jedoch in Form ihrer pharmazeutisch verträglichen Ester, insbesondere als Triglyceride, eingesetzt.The conjugated linoleic acids (CLA) can be produced by isomerization from linoleic acid according to processes known per se. During the isomerization, the double bonds are first shifted from position 9 to position 10 or from position 12 to position 11, reversing the eis, eis into the eis, trans or trans, cw formation. With this shift, 8 different geometric isomers are theoretically possible. The double bonds can shift to other positions during the isomerization processes. Ice, tra / w formation conversions can occur simultaneously, so that a larger number of positional isomers are formed. One of these isomers specifically inhibits the zl 6 desaturation of linoleic acid. According to the invention, the CLA are used in the form of their free acids, but preferably in the form of their pharmaceutically acceptable esters, in particular as triglycerides.
ω-3 -Fettsäuren kommen bekanntlich in Fischölen im Triglyceridverband vor. Fischöle sind besonders reich an EPA und DHA, sie können aber auch Docosapentaensäure (DPA) enthalten. Diese ω-3 -Fettsäuren bzw. die entsprechenden Triglyceride lassen sich aus Fischölen in an sich bekannter Weise isolieren.As is well known, ω-3 fatty acids are found in fish oils in a triglyceride association. Fish oils are particularly rich in EPA and DHA, but they can also contain docosapentaenoic acid (DPA). These ω-3 fatty acids or the corresponding triglycerides can be isolated from fish oils in a manner known per se.
Die ω-3 -Fettsäuren werden erfindungsgemäß in Form ihrer freien Säure oder ihrer pharmazeutisch verträglichen Ester, bevorzugt jedoch im Triglyceridverband, eingesetzt. Vorzugsweise enthalten die erfindungsgemäß verwendeten ω-3 -Fettsäuren 15-50 Gew.-% EPA, 10-50 Gew.-% DHA und 2-8 Gew.-% DPA im Triglyceridverband. Soll das Kombinationspräparat parenteral verabreicht werden, ist es besonders vorteilhaft, die ω-3 -Fettsäuren als im Triglyceridverband angereicherte Fischöle einzusetzen. Die Herstellung deratig hochraffinierter Fischöle wird z.B. in der DE 37 22 540 beschrieben.According to the invention, the ω-3 fatty acids are used in the form of their free acid or their pharmaceutically acceptable esters, but preferably in a triglyceride dressing. The ω-3 fatty acids used according to the invention preferably contain 15-50% by weight EPA, 10-50% by weight DHA and 2-8% by weight DPA in the triglyceride dressing. If the combination preparation is to be administered parenterally, it is particularly advantageous to use the ω-3 fatty acids as fish oils enriched in the triglyceride dressing. The production of such highly refined fish oils is described, for example, in DE 37 22 540.
Die Herstellung eines therapeutisch wirksamen Kombinationspräparats erfolgt so, daß die beiden wirksamen Komponenten, nämlich einerseits ω-3 -Fettsäuren oder deren pharmazeutisch verträgliche Ester oder ein an ω-3 -Fettsäuren im Triglyceridverband angereichertes Fischöl und andererseits die konjugierten Linolsauren (CLA) oder deren pharmazeutisch verträgliche Ester bzw. Triglyceride in vorbestimmtem Mengenverhältnis zu einer Fettemulsion verarbeitet werden, die dann entweder oral oder parenteral dem Patienten zugeführt wird.A therapeutically effective combination preparation is produced in such a way that the two active components, namely on the one hand ω-3 fatty acids or their pharmaceutically acceptable esters or a fish oil enriched in ω-3 fatty acids in a triglyceride dressing and on the other hand the conjugated linoleic acids (CLA) or their pharmaceuticals compatible esters or triglycerides are processed in a predetermined quantitative ratio to form a fat emulsion which is then administered to the patient either orally or parenterally.
In dem Kombinationspräparat soll das Gewichtsverhältnis von ω-3 -Fettsäuren und/oder deren pharmazeutisch verträglichen Salzen und/oder Estern zu den konjugierten Linolsauren (CLA) und/oder deren pharmazeutisch verträglichen Salzen und/oder Estern vorzugsweise im Bereich von 1 :5 bis 10:1 liegen, am meisten bevorzugt bei 1 :1. Werden die ω-3 -Fettsäuren in Form von im Triglyceridverband angereichertem Fischöl eingesetzt und die CLA in Form von pharmazeutisch verträglichen Estern, wie Triglyceriden, liegt das gewichtsprozentuale Verhältnis von angereichertem Fischöl zu CLA oder ihren Estern vorzugsweise im Bereich von 1 :5 bis 20:1.In the combination preparation, the weight ratio of ω-3 fatty acids and / or their pharmaceutically acceptable salts and / or esters to the conjugated linoleic acids (CLA) and / or their pharmaceutically acceptable salts and / or esters should preferably be in the range from 1: 5 to 10 : 1, most preferably 1: 1. If the ω-3 fatty acids are used in the form of fish oil enriched in the triglyceride dressing and the CLA in the form of pharmaceutically acceptable esters, such as triglycerides, the ratio by weight of enriched fish oil to CLA or their esters is preferably in the range from 1: 5 to 20: 1.
In einer bevorzugten Ausfuhrungsform werden 0,3-40 Gew.-% ω-3 -Fettsäuren in Form ihrer Derivate, vorzugsweise in Form der ft>-3-Fettsäuretrigiyceride, oder 0,5-40 Gew.-% eines 25- 80% ω-3 -Fettsäuren im Triglyceridverband enthaltenden Fischöls und 0,5-20 Gew.-% CLA und/oder deren Derivate, vorzugsweise in Form ihrer Triglyceride, als Komponenten eingesetzt.In a preferred embodiment, 0.3-40% by weight of ω-3 fatty acids in the form of their derivatives, preferably in the form of the ft> -3 fatty acid triglycerides, or 0.5-40% by weight of a 25-80% Fish oil containing ω-3 fatty acids in the triglyceride dressing and 0.5-20% by weight of CLA and / or their derivatives, preferably in the form of their triglycerides, are used as components.
Vorzugsweise werden die Komponenten gleichzeitig oder nacheinander vorbestimmten Substraten zugesetzt und in diesen homogen verteilt. Vorzugsweise werden als Substrate feste (bei oraler Applikation) oder flüssige Lebensmittel eingesetzt. Desweiteren werden vorzugsweise solche Lebensmittel eingesetzt, die selbst einen gewissen Fettanteil aufweisen, der vorzugsweise bei 5-30% liegen soll. Andere bevorzugte Substrate sind W/O-Emulsionen und O/W-Emulsionen . insbesondere solche, die für Infusionen geeignet sind, sowie bei oraler Applikation auch Weichgelatinekapseln, in welche die beiden wirksamen Komponenten desThe components are preferably added simultaneously or successively to predetermined substrates and homogeneously distributed therein. Solid (in the case of oral application) or liquid foods are preferably used as substrates. Furthermore, those foods are preferably used which themselves have a certain fat content, which should preferably be 5-30%. Other preferred substrates are W / O emulsions and O / W emulsions. especially those that are suitable for infusions, as well as oral ones Application also soft gelatin capsules, in which the two effective components of the
Präparats gemeinsam oder getrennt voneinander eingeschlossen werden.Preparation be included together or separately.
Eine O/W-Infusionsemulsion für parenterale Verabreichung enthält zusätzlich noch für Injektionszwecke geeignetes destilliertes Wasser, 1-2 Gew.-% Eilecithin und 2-3 Gew.-% Glycerin, wobei 1-30 Gew.-%, vorzugsweise 1,5-20 Gew.-%, der Emulsion durch die erfindungsgemäße Kombination aus ω-3 -Fettsäuren und CLA-Triglyceriden besteht. Wird als Neutralöl ein Fischöl eingesetzt, braucht wegen des Gehalts der darin enthaltenen ω-3- Fettsäuretriglyceride nur noch CLA-Triglyceride in der zur Erreichung des gewünschten Gewichtsverhältnisses von ω- 3 -Fettsäuren zu CLA erforderlichen Menge zugesetzt werden. An O / W infusion emulsion for parenteral administration additionally contains distilled water suitable for injections, 1-2% by weight egg lecithin and 2-3% by weight glycerin, 1-30% by weight, preferably 1.5% 20 wt .-%, the emulsion consists of the combination of ω-3 fatty acids and CLA triglycerides according to the invention. If a fish oil is used as neutral oil, only CLA triglycerides need be added in the amount necessary to achieve the desired weight ratio of ω-3 fatty acids to CLA due to the content of the ω-3 fatty acid triglycerides contained therein.

Claims

Patentansprüche claims
1. Verwendung von ω- 3 -Fettsäuren und/oder deren pharmazeutisch verträglichen Salzen und/oder Estern und/oder einem an ω-3 -Fettsäuren im Triglyceridverband angereicherten Fischöl zusammen mit konjugierten Linolsauren (CLA) und/oder deren pharmazeutisch verträglichen Salzen und/oder Estern zur Herstellung eines Arzneimittels mit immunmodulatorischer und antiinflammatorischer Wirkung gegen Krankheiten mit immunologischer Ausprägung.1. Use of ω-3 fatty acids and / or their pharmaceutically acceptable salts and / or esters and / or a fish oil enriched in ω-3 fatty acids in a triglyceride association together with conjugated linoleic acids (CLA) and / or their pharmaceutically acceptable salts and / or esters for the manufacture of a medicament with immunomodulatory and anti-inflammatory activity against diseases with an immunological expression.
2. Verwendung nach Anspruch 1, wobei <j>3-Fettsäuretriglyceride als <s>3-Fettsäureester eingesetzt werden.2. Use according to claim 1, wherein <j> 3-fatty acid triglycerides are used as <s> 3-fatty acid esters.
3. Verwendung nach Anspruch 1, wobei an ω-3 -Fettsäuren im Triglyceridverband angereichertes Fischöl eingesetzt wird.3. Use according to claim 1, wherein fish oil enriched in ω-3 fatty acids in the triglyceride dressing is used.
4. Verwendung nach Anspruch 1 oder 2, wobei das Gewichtsverhältnis von ω-3- Fettsäuren und/oder deren pharmazeutisch verträglichen Salzen und/oder Estern zu den konjugierten Linolsauren (CLA) und/oder deren pharmazeutisch verträglichen Salzen und/oder Estern im Bereich von 1 :5 bis 10:1 liegt.4. Use according to claim 1 or 2, wherein the weight ratio of ω-3 fatty acids and / or their pharmaceutically acceptable salts and / or esters to the conjugated linoleic acids (CLA) and / or their pharmaceutically acceptable salts and / or esters in the range of 1: 5 to 10: 1.
5. Verwendung nach Anspruch 4, wobei das Gewichtsverhältnis von ω-3 -Fettsäuren und/oder deren pharmazeutisch verträglichen Salzen und/oder Estern zu den konjugierten Linolsauren (CLA) und/oder deren pharmazeutisch verträglichen Salzen und/oder Estern 1 : 1 ist.5. Use according to claim 4, wherein the weight ratio of ω-3 fatty acids and / or their pharmaceutically acceptable salts and / or esters to the conjugated linoleic acids (CLA) and / or their pharmaceutically acceptable salts and / or esters is 1: 1.
6. Verwendung nach Anspruch 3, wobei das Gewichtsverhältnis von an ω-3 -Fettsäuren im Triglyceridverband angereichertem Fischöl zu den konjugierten Linolsauren (CLA) in Form von deren pharmazeutisch verträglichen Estern im Bereich von 1 :5 bis 20:1 liegt. 6. Use according to claim 3, wherein the weight ratio of fish oil enriched in ω-3 fatty acids in the triglyceride dressing to the conjugated linoleic acids (CLA) in the form of their pharmaceutically acceptable esters is in the range from 1: 5 to 20: 1.
7. Verwendung nach einem der Ansprüche 1 bis 6, wobei die eingesetzten ω-3 -Fettsäuren sich aus 15-50 Gew.-% EPA, 10-50 Gew.-% DHA und 2-8 Gew.-% DPA zusammensetzen.7. Use according to one of claims 1 to 6, wherein the ω-3 fatty acids used are composed of 15-50 wt .-% EPA, 10-50 wt .-% DHA and 2-8 wt .-% DPA.
8. Verwendung nach Anspruch 1, wobei 0,3-40 Gew.-% der ω-3 -Fettsäuren in Form ihrer Triglyceride und 0,5-20 Gew.-% CLA in Form ihrer pharmazeutisch verträglichen Ester eingesetzt werden.8. Use according to claim 1, wherein 0.3-40% by weight of the ω-3 fatty acids in the form of their triglycerides and 0.5-20% by weight of CLA in the form of their pharmaceutically acceptable esters are used.
9. Verwendung nach Anspruch 1, wobei 0,5-40 Gew.-% eines 25-80% ω-3 -Fettsäuren im Triglyceridverband enthaltenden Fischöls und 0,5-20 Gew.-% CLA in Form ihrer Triglyceride eingesetzt werden.9. Use according to claim 1, wherein 0.5-40 wt .-% of a 25-80% ω-3 fatty acids in the triglyceride-containing fish oil and 0.5-20 wt .-% CLA are used in the form of their triglycerides.
10. Verwendung nach einem der Ansprüche 1 bis 9 zum Einsatz gegen Psoriasis.10. Use according to one of claims 1 to 9 for use against psoriasis.
11. Verwendung nach einem der Ansprüche 1 bis 9 zum Einsatz gegen zystische Fibröse. 11. Use according to one of claims 1 to 9 for use against cystic fibrosis.
EP01929617A 2000-05-05 2001-05-03 Combination preparation consisting of omega-3-fatty acids and of conjugated linoleic acids for treating immunologically oriented clinical signs Revoked EP1296669B1 (en)

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PCT/EP2001/005011 WO2001085161A1 (en) 2000-05-05 2001-05-03 Combination preparation consisting of φ-3-fatty acids and of conjugated linoleic acids for treating immunologically oriented clinical signs

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EP01929617A Revoked EP1296669B1 (en) 2000-05-05 2001-05-03 Combination preparation consisting of omega-3-fatty acids and of conjugated linoleic acids for treating immunologically oriented clinical signs

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EP (1) EP1296669B1 (en)
AT (1) ATE312604T1 (en)
AU (1) AU2001256334A1 (en)
DE (1) DE50108392D1 (en)
DK (1) DK1296669T3 (en)
ES (1) ES2250397T3 (en)
WO (1) WO2001085161A1 (en)

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Publication number Priority date Publication date Assignee Title
DE10329839A1 (en) * 2003-06-04 2005-01-05 Hogl, Peter Use of artificial nutrition solutions to treat skin diseases, especially psoriasis, neurodermatitis, acne, dermatoses or eczema
NZ543486A (en) * 2005-11-10 2009-03-31 Fonterra Corporate Res And Dev Compositions of CIS-9, trans-11 conjugated linoleic acid and vaccenic acid and uses thereof

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Publication number Priority date Publication date Assignee Title
DK0637957T3 (en) * 1992-04-28 1997-08-18 Fresenius Ag Use of an Omega-3 Fatty Acid Emulsion to Prepare a Drug for Parenteral Treatment of Inflammatory Diseases
DE4432633C2 (en) * 1994-09-14 1997-07-31 Singer Peter Dr Med Priv Doz Pharmaceutical preparation for the local treatment of psoriasis, atopic dermatitis and eczema
GB9621630D0 (en) * 1996-10-17 1996-12-11 Kappa Pharmaceuticals Ltd Treatment of skin disorders
AU728842B2 (en) * 1997-08-18 2001-01-18 South Dakota State University Dairy products with enhanced CLA content

Non-Patent Citations (1)

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Title
See references of WO0185161A1 *

Also Published As

Publication number Publication date
EP1296669B1 (en) 2005-12-14
AU2001256334A1 (en) 2001-11-20
DE50108392D1 (en) 2006-01-19
DK1296669T3 (en) 2006-04-18
ATE312604T1 (en) 2005-12-15
WO2001085161A1 (en) 2001-11-15
ES2250397T3 (en) 2006-04-16

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